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bioRxiv · 10.64898/2026.06.30.732683

Trans-presentation of IL-15 by IL15Rα attenuates tumor immune surveillance and is dispensable for IL-15-dependent tumor growth control

Rexhepi, F.·Ali Akbari, S.·Moradzad, M.·Khodayari, S.·Shukla, A.·Demontier, E.·Armas Cayarga, A.·Allard-Chamard, H.·Ilangumaran, S.·Ramanathan, S.
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Abstract

BackgroundIL-15 is a promising cytokine for cancer immunotherapy. IL-15 promotes differentiation and homeostasis of innate and adaptive immune cells, and their cytolytic effector functions. IL-15 receptor is composed of IL-15R, IL-15R{beta} and the common {gamma}c chains. IL-15 is also trans-presented as IL-15R:IL-15 complex to IL-15R{beta}:{gamma}c on neighboring cells. IL-15R is dispensable for early immune response to infections and in autoimmune diabetes. The role of IL-15R in antitumor immune responses remains unclear. MethodsIn WT, Il15-/- and Il15ra-/- mice, we studied the growth of syngeneic tumor cell lines and tumor immune surveillance against endogenous fibrosarcoma induced by methylcholanthrene (MCA). Immune gene signature and total proteome analysis were performed on MCA-induced tumors. ResultsLack of IL-15 or IL-15R did not enhance the growth of implanted tumor cell lines, despite reduced immune cell infiltration. MCA-induced tumor incidence was reduced in mice lacking IL-15R but not IL-15, although both are required for efficient tumor immunoediting. Il15-/- and Il15ra-/- tumors showed reduced Ifng expression but displayed differential modulation of Ifng-responsive genes. Proteome profiles of Il15-/- tumors, but not tumor-derived cell lines, showed significant reduction of antigen presentation pathways. B16-F10 melanoma cells expressing NLRC5, the IFN{gamma}-induced transcriptional activator of tumor antigen presentation, still required IL-15 but not IL-15R for efficient tumor control. ConclusionsOur findings show that IL-15 plays a negligible role in immunosurveillance against spontaneous tumor development, whereas IL-15R restrains immunosurveillance. Neither IL-15 nor IL-15R have a significant impact on implanted tumor models, although IL-15 facilitates efficient control of highly immunogenic tumors for which IL-15R is dispensable.

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Rexhepi, F., Ali Akbari, S., Moradzad, M., Khodayari, S., Shukla, A., Demontier, E., Armas Cayarga, A., Allard-Chamard, H., Ilangumaran, S., Ramanathan, S.. 2026-07-03. Trans-presentation of IL-15 by IL15Rα attenuates tumor immune surveillance and is dispensable for IL-15-dependent tumor growth control. https://doi.org/10.64898/2026.06.30.732683

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